Extended Release Tablet Formulation Containing Pramipexole or a Pharmaceutically Acceptable Salt Thereof

ABSTRACT

An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water swelling polymer other than pregelatinized starch.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/202,713, filedAug. 12, 2005, which claims priority, as does the present application,to European Application No. 04019248.6 filed Aug. 13, 2004, both ofwhich are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to an extended release tabletformulation containing pramipexole or a pharmaceutically acceptable saltthereof, a method for manufacturing the same, and use thereof

BACKGROUND OF THE INVENTION

Pramipexole is a known dopamine D2 receptor agonist. It is structurallydifferent from the ergot-derived drugs, e.g., bromocriptine orpergolide. It is also pharmacologically unique in that it is a fullagonist and has receptor selectivity for the dopamine D2 family ofdopamine receptors.

Pramipexole is designated chemically as(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and has themolecular formula C₁₀H₁₇N₃S and a relative molecular mass of 211.33. Thechemical formula is as follows:

The salt form commonly used is pramipexole dihydrochloride monohydrate(molecular formula C₁₀H₂₁Cl₂N₃OS; relative molecular mass 302.27).Pramipexole dihydrochloride monohydrate is a white to off-white,tasteless, crystalline powder. Melting occurs in the range of 296° C. to301° C., with decomposition. Pramipexole is a chiral compound with onechiral center. Pure (S)-enantiomer is obtained from the syntheticprocess by chiral recrystallization of one of the intermediates duringsynthesis.

Pramipexole dihydrochloride monohydrate is a highly soluble compound.Water solubility is more than 20 mg/mL and solubility in buffer media isgenerally above 10 mg/mL between pH 2 and pH 7.4. Pramipexoledihydrochloride monohydrate is not hygroscopic, and has a highlycrystalline nature. Under milling, the crystal modification(monohydrate) does not change. Pramipexole is very stable in the solidstate, yet in solution it is light sensitive.

Pramipexole immediate release (IR) tablets were first authorized in theUSA in 1997, followed over the course of the next years by marketingauthorizations in the European Union (EU), Switzerland, Canada, andSouth America as well as in countries in Eastern Europe, the Near East,and Asia.

Pramipexole IR tablets are indicated in the EU and US for the treatmentof signs and symptoms of either early Parkinson's Disease or advancedParkinson's Disease in combination with levodopa. The IR tablets have tobe taken 3 times a day.

From the pharmacokinetic point of view, pramipexole IR tablets arerapidly and completely absorbed following oral administration. Theabsolute bioavailability is greater than 90% and the maximum plasmaconcentration occurs within 1 to 3 hours. The rate of absorption isreduced by food intake but not the overall extent of absorption.Pramipexole shows linear kinetics and a relatively small inter-patientvariation of plasma levels. The elimination half-life (t_(1/2)[h])varies from 8 hours in the young to 12 hours in the elderly.

As is commonly known, modified release of active ingredient(s) allowssimplification of the patient's administration scheme by reducing theamount of recommended daily intakes, improves patient's compliance, andattenuates adverse events, e.g., related to high plasma peaks. Modifiedrelease pharmaceutical preparations regulate the release of theincorporated active ingredient or ingredients over time and compriseformulations with a controlled, a prolonged, a sustained, a delayed, aslow or an extended release, so they accomplish therapeutic orconvenience objectives not offered by conventional dosage forms such assolutions or promptly dissolving dosage forms.

A modified or extended release of active ingredient(s) from apharmaceutical preparation may be accomplished by homogeneouslyembedding the active ingredient(s) in a hydrophilic matrix, being asoluble, partially soluble or insoluble network of viscous, hydrophilicpolymers, held together by physical or chemical entanglements, by ionicor crystalline interactions, by complex formation, by hydrogen bonds orvan der Waals forces. The hydrophilic matrix swells upon contact withwater, thereby creating a protective gel layer from which the activeingredient(s) are slowly, gradually, continuously released in timeeither by diffusion through the polymeric network, by erosion of the gellayer, by dissolution of the polymer, or by a combination of theserelease mechanisms.

However, it has proved difficult to formulate a tablet having a suitablecombination of modified, extended or sustained-release and handlingproperties, where the drug is one having relatively high solubility, asin the case of pramipexole dihydrochloride.

There are a number of approaches described in prior art to providesustained release tablet compositions of pramipexole.

WO 2004/010997 describes a sustained-release pharmaceutical compositionin a form of an orally deliverable tablet comprising a water-solublesalt of pramipexole, dispersed in a matrix comprising a hydrophilicpolymer and a starch having a tensile strength of at least about 0.15 kNcm⁻², preferably at least about 0.175 kN cm⁻², and more preferably atleast about 0.2 kN cm⁻², at a solid fraction representative of thetablet. The disclosure thereof is concentrated to provide a compositionwith sufficient hardness yield during a high-speed tabletting operation,in particular to resist erosion during application of a coating layer.According to a preferred embodiment it is provided a pharmaceuticalcomposition in a form of an orally deliverable tablet having a corecomprising pramipexole dihydrochloride monohydrate in an amount of about0.375, 0.75, 1.5, 3, or 4.5 mg, dispersed in a matrix comprising (a)HPMC type 2208 in an amount of about 35% to about 50% by weight of thetablet and (b) a pregelatinized starch having a tensile strength of atleast about 0.15 kN cm⁻² at a solid fraction of 0.8, in an amount ofabout 45% to about 65% by weight of the tablet; the core beingsubstantially enclosed in a coating that constitutes about 2% to about7% of the weight of the tablet, the coating comprising an ethylcellulose-based hydrophobic or water-insoluble component and anHPMC-based pore-forming component in an amount of about 10% to about 40%by weight of the ethyl cellulose-based component.

Furthermore, WO 2004/010999 discloses an orally deliverablepharmaceutical composition comprising a therapeutically effective amountof pramipexole or a pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient, the compositionexhibiting at least one of (a) an in vitro release profile wherein onaverage no more than about 20% of the pramipexole is dissolved within 2hours after placement of the composition in a standard dissolution test;and (b) an in vivo pramipexole absorption profile following single doseoral administration to healthy adult humans wherein the time to reach amean of 20% absorption is greater than about 2 hours and/or the time toreach a mean of 40% absorption is greater than about 4 hours. However,in practical use, it appears that any formulation having an extended orcontrolled release profile designed for a once daily application wouldmeet the above requirements for which a general teaching how to adjustsuch a profile is missing.

It is an object of the present invention to provide a controlled releasetablet composition of pramipexole or a pharmaceutically acceptable saltthereof that is suitable for once-daily oral administration. It is afurther object to provide a tablet composition comprising pramipexole ora pharmaceutically acceptable salt thereof that provides a day-longtherapeutic effect and will allow patients to treat their symptoms witha single daily dose, which makes it possible to adjust the releaseprofile of the active ingredient according to a selected release profiledependent or independent from the pH values. Furthermore a method ofmanufacturing the tablet formulation shall be provided.

DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that pramipexole or a pharmaceuticallyacceptable salt thereof may be used in formulations as once dailyextended (or slow) release tablets and two alternative formulationprinciples allow different release rate types dependent or independentfrom the pH value.

The present invention relates to an extended release tablet formulationcomprising pramipexole or a pharmaceutically acceptable salt thereof ina matrix comprising at least one water swelling polymer other thanpregelatinized starch.

Preferably the invention relates to an extended release tabletformulation, wherein the matrix comprises at least two water swellingpolymers other than pregelatinized starch, and wherein at least one ofthe at least two polymers is an anionic polymer.

Also preferred is an extended release tablet formulation, wherein theanionic polymer is selected from the group of optionally crosslinkedacrylic acid polymers, methacrylic acid polymers, alginates, andcarboxymethyl cellulose.

Also preferred is an extended release tablet formulation, wherein theanionic polymer is an optionally crosslinked acrylic acid polymer, andwherein the content of the optionally crosslinked acrylic acid polymerin the matrix is from about 0.25 wt.-% to about 25 wt.-%, and preferablyfrom about 0.5 wt.-% to about 15 wt.-%, and preferably from about 1wt.-% to about 10 wt.-%.

Also preferred is an extended release tablet formulation, wherein atleast one of the at least two polymers is a substantially neutralpolymer other than pregelatinized starch.

Also preferred is an extended release tablet formulation, wherein thesubstantially neutral polymer is selected from hydroxypropyl celluloseand hydroxypropyl methyl cellulose.

Particularly preferred is an extended release tablet formulation,wherein the substantially neutral polymer is hydroxypropyl methylcellulose, and wherein the content of hydroxypropyl methyl cellulose inthe matrix is from about 10 wt.-% to about 75 wt.-% and preferably fromabout 25 wt.-% to about 65 wt.-%.

Particularly preferred is an extended release tablet formulation,wherein the matrix comprises about:

(a) 0.05 to 5 wt.-% of pramipexole or a salt thereof,

(b) 0.25 to 25 wt.-% of anionic water swelling polymer(s);

(c) 10 to 75 wt.-% of neutral water swelling polymer(s); and

(d) further excipients to 100 wt.-%

Particularly preferred is an extended release tablet formulationconsisting of pramipexole dihydrochloride monohydrate, Hypromellose2208, corn starch, Carbomer 941, colloidal silicon dioxide, andmagnesium stearate.

A preferred embodiment of the present invention relates to an extendedrelease tablet formulation comprising pramipexole or a pharmaceuticallyacceptable salt thereof in a matrix comprising:

-   -   (a) at least one water swelling polymer other than        pregelatinized starch and optionally excipients, the resulting        tablet providing a pH-independent in vitro release        characteristic in the range from pH 1 to 7.5, or    -   (b) at least one water swelling anionic polymer and optionally        excipients, the resulting tablet providing a pH-dependent        release characteristic with a faster release characteristic in        the range of pH<4.5, and a slower and further on pH-independent        release characteristic in the range from pH 4.5 to 7.5.

Most preferably the present invention relates to a matrix of theextended release tablet formulation comprising at least one waterswelling polymer other than pregelatinized starch, preferably a waterswelling essentially neutral polymer, a water swelling anionic polymerand optionally excipients, the resulting tablet providing a pH-dependentrelease characteristic with a faster release characteristic in the rangeof pH<4.5, and a slower and further on pH-independent releasecharacteristic in the range from pH 4.5 to 7.

The extended release formulations according to the present inventionintended for oral administration allow to select and estimate which invitro release characteristic and timing of a formulation is mostsuitable to achieve the desired in vivo plasma profiles preferably witha once daily application. Therefore, a formulation principle withseveral variants has been developed for a single unit matrix tablet,i.e., formulations having different release rate types are provided anda different pH dependency is available. These alternative formulationsare beneficial to patients as the extended release drug delivery willallow patients to treat their symptoms with a single daily dose, therebyincreasing patient convenience and compliance.

The term “in vitro release characteristic” as used hereinbefore orhereinafter is directed to a release characteristic as obtained in akind of normally used liquid medium for in vitro experiments wherein therelease of active ingredient from the extended release formulation canoccur, i.e., for example, in in vitro dissolution media, but also inbody fluids or simulated body fluids, more in particular in thegastrointestinal fluids.

In the frame of the present invention the term “extended” release shouldbe understood in contrast to an immediate release, the active ingredientis gradually, continuously liberated over time, sometimes slower orfaster, dependent or independent from the pH value. In particular, theterm indicates that the formulation does not release the full dose ofthe active ingredient immediately after oral dosing and that theformulation allows a reduction in dosage frequency, following thedefinition for extended release, interchangeable with slow release. Aslow or extended release, used synonymously with prolonged action,sustained release, or modified release, dosage form is a dosage formthat allows a reduction in dosing frequency or a significant increase inpatient compliance or therapeutic performance as compared to thatpresented as a conventional dosage form (e.g., as a solution or animmediate drug-releasing, conventional solid dosage form).

A release characteristic which is pH-independent indicates that therelease characteristic is virtually the same in different pH media.

According to the teaching of the present invention, extended releasetablet formulations are provided with different in vitro releaseprofiles.

The extended release tablets of the present invention are believed toapply a swelling and partly eroding polymer matrix. Based on the assumedmechanisms, the release profile may roughly follow a square root of timeto exponential in vitro release characteristic. Depending on theparticular embodiment formulation a) is widely independent from the pHvalue in the range from pH 1 to 7.5, and formulation b) is faster insimulated gastric juice having a pH<4.5 but are independent from the pHvalue in the range from 4.5 to 7.5. A faster release in simulatedgastric juice versus slower release in the intestinal fluid can beadvantageous in cases where a loading dose effect from the dosage formis desired, whereas a widely pH independent release profile can beadvantageous to reduce the risk of dose dumping and food effects.

According to the present invention under “formulation a)” is understoodthe tablet formulation wherein the matrix comprises the composition asabove-defined under a) and under “formulation b)” is understood thetablet formulation wherein the matrix comprises the composition asabove-defined under b).

The water swelling polymer of the present invention represents at leastone hydrophilic water swelling polymer constituting the extended releasematrix which slowly releases the pramipexole or its salt as activeingredient. The polymer swells upon contact with aqueous fluid followingadministration, resulting in a viscous, drug release regulating gellayer. The viscosity of the polymer preferably ranges from 150 to100,000 mpa·s (apparent viscosity of a 2% aqueous solution at 20° C.).

Examples of such polymers are water swelling substantially neutralpolymers or water swelling anionic polymers.

The term “water swelling substantially neutral polymers” of the presentinvention comprises alkyl celluloses such as methyl cellulose;hydroxyalkyl celluloses, for example, hydroxymethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutylcellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methylcellulose and hydroxypropyl methyl cellulose; carboxyalkyl celluloseesters; other natural, semi-synthetic, or synthetic di-, oligo-, andpolysaccharides such as galactomannans, tragacanth, agar, guar gum, andpolyfructans; methacrylate copolymers; polyvinyl alcohol;polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; andpolyalkylene oxides such as polyethylene oxide and polypropylene oxideand copolymers of ethylene oxide and propylene oxide, preferablycellulose ether derivatives such as hydroxypropyl methyl cellulose andhydroxypropyl cellulose, most preferred hydroxypropyl methyl cellulose.

The term “water swelling anionic polymer” of the present inventioncomprises acrylic acid polymerisate, methacrylic acid copolymers,alginates, carrageenans, acacia, xanthan gum, chitin derivates such aschitosan, carmellose sodium, and carmellose calcium, preferably acrylicacid polymerisate.

Different viscosity grades of hydroxypropyl cellulose and hydroxypropylmethyl cellulose are commercially available. Hydroxypropyl methylcellulose (HPMC) preferably used in the present invention has aviscosity grade ranging from about 3,500 mPa·s to about 100,000 mPa·s,in particular ranging from about 4,000 mPa·s to about 20,000 mPa·s andmost in particular a viscosity grade of about 6,500 mPa·s to about15,000 mPa·s (apparent viscosity of a 2% aqueous solution at 20° C.),e.g., hypromellose 2208 or 2206 (DOW, Antwerp, Belgium). HPMC type 2208contains 19-24% by weight methoxy and 4-12% by weight hydroxypropoxysubstituents.

Hydroxypropyl cellulose having a viscosity higher than 1,500 mPa·s(apparent viscosity of a 1% aqueous solution at 20° C.) is preferred, inparticular hydroxypropyl cellulose having a viscosity in the range fromabout 1500 to about 3000 mPa·s, preferably from 4000 to 6500 mPa·s (2%aqueous solutions), e.g., the Klucel series such as Klucel M (Hercules,Wilmington, USA).

Without wishing to be bound by theory, there are believed to exist threemain mechanisms by which pramipexole or a salt thereof can be releasedfrom a hydrophilic matrix: dissolution, erosion and diffusion.Pramipexole or its salt will be released by the dissolution mechanismwhen it is homogeneously dispersed in a matrix network of a solublepolymer. The network will gradually dissolve in the gastrointestinaltract, thereby gradually releasing its load. The matrix polymer can alsogradually be eroded from the matrix surface, likewise releasingpramipexole or its salt in time. When pramipexole is processed in amatrix made up of an insoluble polymer, it will be released bydiffusion: the gastrointestinal fluids penetrate the insoluble,sponge-like matrix and diffuse back out loaded with drug.

Therefore, the water swelling polymers constituting the matrix,particularly in a matrix according to formulation a), mainly provide forthe controlled pharmacokinetic release profile of the preparation.Depending on the amount of water swelling polymer(s) processed in thepreparation, the release profile can be tuned, i.e., larger amounts ofswelling polymer lead to a more pronounced sustained release effect andvice versa. Preferably, the amount of water swelling polymer in thepresent formulation ranges from about 10 to about 80% by weight.

In addition, when using a combination of polymers, the ratio of thepolymers also influences the release profile of the preparation. Acombination of different polymers offers the possibility of combiningdifferent mechanisms by which pramipexole is released from the matrix.Such combination facilitates control of the pharmacokinetic releaseprofile of the preparation at will. For example, when using one or morewater swelling polymers, in particular hydroxypropyl cellulose andhydroxypropyl methyl cellulose, the weight percentage of hydroxypropylmethyl cellulose preferably ranges from 25 to about 62%; the weightpercentage of hydroxypropyl cellulose preferably ranges between 0% andabout 16%.

Release of pramipexole or a salt thereof from a matrix containinghydroxypropyl cellulose and hydroxypropyl methyl cellulose occurs by acombined set of release mechanisms. Due to the higher solubility ofhydroxypropyl methyl cellulose compared with hydroxypropyl cellulose,the former will gradually dissolve and erode from the matrix, whereasthe latter will more act as a sponge-like matrix former releasing theactive ingredient mainly by diffusion.

The extended release tablet formulation according to formulation a) ispH-independent. Therefore, the disadvantage that food relateddose-dumping may be encountered is avoided. The problem of food relateddose-dumping in fed patients can be attributed to a lot of factors suchas the mechanical forces that are exerted by the stomach on its contentand thus on an ingested preparation as well as the different pH regionsof the gastrointestinal tract. Since the pH values encountered in thegastrointestinal tract vary not only with the region of the tract, butalso with the intake of food, an extended release formulation preferablyalso has to provide an extended release profile and in particular has toavoid dose-dumping regardless whether the patient is in fasted or fedconditions.

According to the present invention the oral extended release formulationa) retains its pharmacokinetic release profile along its way through thegastrointestinal tract so as to avoid undesirable fluctuations in drugplasma concentrations or complete dose-dumping, in particular avoidsdose-dumping in different regions of the gastrointestinal tract.

Beside pramipexole or a salt thereof, and the water swelling polymer(s),the formulation of the present invention may also optionally comprisefurther excipients, i.e., pharmaceutically acceptable formulatingagents, in order to promote the manufacture, compressibility,appearance, and taste of the preparation. These formulating agentscomprise, for example, diluents or fillers, glidants, binding agents,granulating agents, anti-caking agents, lubricants, flavors, dyes, andpreservatives. Other conventional excipients known in the art can alsobe included.

The filler may be selected from soluble fillers, for example, sucrose,lactose, in particular lactose monohydrate, trehalose, maltose, mannitoland sorbitol. Different grades of lactose can be used. One type oflactose preferably used in the present invention is lactose monohydrate200 mesh (DMV, Veghel, The Netherlands). Another lactose monohydrate,lactose monohydrate of the type DCL 11 (DMV, Veghel, The Netherlands),can also preferably be used. The notation DCL refers to “DirectCompression Lactose”. The number 11 is a reference number of themanufacturer. In case of a water soluble active ingredient, like the onedescribed in this invention, more preferably water insoluble fillers,such as starch and starch derivates other than pregelatinized starch,e.g., corn starch, potato starch, rice starch or wheat starch,microcrystalline cellulose, dibasic calcium phosphate dihydrate, andanhydrous dibasic calcium phosphate, preferably corn starch, can be usedin addition or instead of the water soluble fillers. The total weightpercentage of filler ranges between about 5% and about 75% by weight.

A glidant can be used to improve powder flow properties prior to andduring tabletting and to reduce caking. Suitable glidants includecolloidal silicon dioxide, magnesium trisilicate, powdered cellulose,talc, tribasic calcium phosphate and the like. Colloidal silicon dioxideis preferably included as a glidant in an amount up to about 2%,preferably about 0.2% to about 0.8%, by weight of the tablet.

A lubricant can be used to enhance release of a tablet from apparatus onwhich it is formed, for example by preventing adherence to the face ofan upper punch (“picking”) or lower punch (“sticking”). Suitablelubricants include magnesium stearate, calcium stearate, canola oil,glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide,mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodiumbenzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid,talc, hydrogenated vegetable oil, zinc stearate and the like. In oneembodiment, magnesium stearate is included as a lubricant in an amountof about 0.1% to about 1.5%, preferably about 0.3% to about 1%, byweight of the tablet.

Among the optional formulating agents that further may be comprised inthe matrix formulation there may be mentioned agents such as polyvidone;copovidone; starch; acacia; gelatin; seaweed derivatives, e.g., alginicacid, sodium and calcium alginate; cellulose, preferablymicrocrystalline cellulose, cellulose derivatives, e.g., ethylcellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose,having useful dry or wet binding and granulating properties; andantiadherents such as talc and magnesium stearate.

According to a preferred embodiment of the present invention the matrixof the extended release tablet formulation of alternative a) comprisesor essentially consists of hydroxypropyl methyl cellulose, such ashypromellose, and further excipients. The amount of hydroxypropyl methylcellulose is preferably in the range from 10 to 75%, particularlypreferred from 25 to 65% most preferred from 35 to 55% by weight. Theamount of further excipients is preferably in the range from 90 to 25%,particularly preferred from 75 to 35%, most preferred from 65 to 45% byweight.

The expression “consisting essentially” is understood in the sense thatit does not in principle exclude the presence, in addition to themandatory components mentioned, of other components, the presence ofwhich does not affect the essential nature of the formulation.

In some embodiments of the present invention it is provided apH-dependent release profile, the release of pramipexole or its saltfrom the tablet and subsequent the absorption into the blood stream canvary during the passage of the dosage form along the gastrointestinaltract. Thus, formulation b) provides a pH-dependent releasecharacteristic wherein the release characteristic in the range of pH<4.5is faster and a slower and further on pH-independent releasecharacteristic in the range from 4.5≦pH≦7.5.

The above details for the water swelling polymer and selection and typeof optional excipients may apply to formulation b), too.

Moreover, an anionic water swelling polymer, preferably an acrylic acidpolymerisate is mandatorily present in formulation b), which ispreferably selected from carbomer or CARBOPOL® series, known acrylicacid polymerisates having high molecular weights. Particularly preferredare, for example, carbomer 941 (CARBOPOL® 71 G, CARBOPOL® 971) andcarbomer 934 (CARBOPOL® 974). The acrylic acid polymerisate ispreferably present in the range of 0.25 to 25% by weight, particularlypreferred 0.5 to 15% by weight, most preferred 1 to 10% by weight. ThepH dependency of formulation b) results from the presence of an anionicwater swelling polymer, particularly preferred from the presence ofacrylic acid polymerisate which intends to swell in a greater extent inthe acid pH range above pH 4.5 and in the alkaline pH range.

An increasing amount of acrylic acid leads to a decrease of the releaserate. Therefore, adjusting the amount of acrylic acid polymerisate makesit possible to further tune the dissolution profiles as desired. Toadjust the amount of acrylic acid polymerisate in the preferred rangefrom 0.25 to 25% by weight provides the further advantage that thedesired, resp. matching, dissolution profiles can be adjusted, resp.maintained, for a variety of formulations composed of different amountsand/or types of gel-forming agents, water swelling polymers, fillers,and dry binders.

According to a preferred embodiment of the present invention the matrixof the extended release tablet formulation comprises or essentiallyconsists of hydroxypropyl methyl cellulose, acrylic acid polymerisateand further excipients. The amount of hydroxypropyl methyl cellulose ispreferably in the range from 10 to 75%, particularly preferred from 25to 65%, most preferred from 35 to 55% by weight. The amount of acrylicacid polymerisate is preferably as abovementioned. The amount ofadditional excipients is preferably in the range from 90 to 25%particularly preferred from 75 to 35%, most preferred from 65 to 45% byweight. Optionally carboxymethyl cellulose sodium may additionally bepresent preferably in the range from 5 to 50%, particularly preferredfrom 10 to 40%, most preferred from 15 to 30% by weight.

As active ingredient, pramipexole or a pharmaceutically acceptable saltthereof, may be present in any amount suitable for the desired treatmentof a patient. A preferred salt of pramipexole is the dihydrochloridesalt, most preferably in the form of the monohydrate.

Usual amounts are from about 0. 1 to about 5 mg of pramipexole salt.According to a particularly preferred embodiment e.g., 0.750 mg ofpramipexole dihydrochloride monohydrate, corresponding to 0.524 mg ofanhydrous base, is used in the extended release tablet formulationaccording to the present invention. However, any other amount of activeingredient suitable for treatment may be used with the only proviso thatthe amount of pramipexole or salt is sufficient to provide a daily dosein one to a small plurality, for example one to about 4, of tablets tobe administered at one time. Preferably the full daily dose is deliveredin a single tablet. An amount of pramipexole salt, expressed aspramipexole dihydrochloride monohydrate equivalent, of about 0.1 toabout 10 mg per tablet, or about 0.05% to about 5% by weight of thecomposition, will generally be suitable. Preferably an amount of about0.2 to about 6 mg, more preferably an amount of about 0.3 to about 5 mg,per tablet is present. Specific dosage amounts per tablet, e.g., include0.375, 0.5, 0.75, 1.0, 1.5, 3.0, and 4.5 mg of pramipexoledihydrochloride monohydrate. The amount that constitutes atherapeutically effective amount varies according to the condition beingtreated, the severity of the condition, and the patient being treated.

An extended release tablet formulation according to the presentinvention, has preferably the following composition:

-   -   (a) 0.05 to 5% by weight of pramipexole or a salt thereof,    -   (b) 10 to 75% by weight water swelling polymer(s);    -   (c) 0 to 25% by weight acrylic acid polymerisate; and    -   (d) to 100% by weight of optional further excipient(s).

Therefore, a particularly preferred extended release tablet formulationof the present invention consists of:

-   -   (a) 0. 1 to 2% by weight of pramipexole or a salt thereof,    -   (b) 25 to 65% by weight of hydroxypropyl methyl cellulose;    -   (c) 0 to 40% by weight of carboxymethyl cellulose sodium;    -   (d) 0 to 75% by weight of corn starch other than pregelatinized        starch;    -   (e) 0 to 15% by weight of acrylic polymerisate, preferably        carbomer 941; and    -   (f) 0.5 to 50% by weight of excipients, preferably selected from        the group consisting of colloidal silicon dioxide, magnesium        stearate, lactose monohydrate, mannitol, microcrystalline        cellulose, dibasic anhydrous calcium phosphate, hydroxypropyl        cellulose, povidone, copovidone, talc, macrogols, sodium        dodecylsulfate, iron oxides, and titanium dioxide.

According to the present invention starch other than pregelatinizedstarch, preferably corn starch if present, may impart several functionsat the same time such as filler, glidant, and the like. However, it maybe preferred to exclude starch completely from the tablet formulationaccording to the present invention, which may be replaced by one or moreof the above-mentioned other excipient(s). Furthermore, a starch havinga tensile strength of at least about 0.15 kN cm⁻² at a solid fractionrepresentative of the tablet as claimed according to WO 2004/010997 isnot required according to the present invention.

It is preferred that no coating is present on the tablet formulationaccording to the present invention. However, the extended release tabletof the invention may comprise a nonfunctional coating. A nonfunctionalcoating can comprise a polymer component, for example HPMC, optionallywith other ingredients, for example, one or more plasticizers,colorants, etc. The term “nonfunctional” in the present context meanshaving no substantial effect on release properties of the tablet, andthe coating serves another useful purpose. For example, such a coatingcan impart a distinctive appearance to the tablet, provide protectionagainst attrition during packaging and transportation, improve ease ofswallowing, and/or have other benefits. A nonfunctional coating shouldbe applied in an amount sufficient to provide complete coverage of thetablet. Typically an amount of about 1% to about 10%, more typically anamount of about 2% to about 5%, by weight of the tablet as a whole, issuitable.

The tablets of the present invention can be of any suitable size andshape, for example round, oval, polygonal, or pillow-shaped, andoptionally bear nonfunctional surface markings. According to the presentinvention it is preferred that the extended release tablets are white tooff-white and of oval or round, biconvex, shape.

Tablets of the invention can be packaged in a container, accompanied bya package insert providing pertinent information such as, for example,dosage and administration information, contraindications, precautions,drug interactions, and adverse reactions.

The present invention is further directed to the use of the extendedrelease tablet formulation according to the present invention forpreparing a medical composition for the treatment of Parkinson's Diseaseand complications or disorders associated therewith.

Furthermore, the present invention is preferably directed to a method ofmanufacturing the extended release tablet formulations via a directcompression process comprising the steps of:

-   -   (1) producing an active ingredient trituration wherein the        active ingredient is pramipexole or a pharmaceutically        acceptable salt thereof by preblending it with a portion of        water swelling polymer(s) and/or further excipient(s) in a        mixer, wherein pramipexole or the pharmaceutically acceptable        salt thereof is milled, preferably peg-milled, prior to use;    -   (2) premixing the active ingredient trituration of step (1), the        main portion of the water swelling polymer(s) and/or excipients        in a mixer to obtain a pre-mixture;    -   (3) optionally dry screening the pre-mixture through a screen in        order to segregate cohesive particles and to improve content        uniformity;    -   (4) mixing the pre-mixture of step (2) or (3) in a mixer,        optionally by adding remaining excipients to the mixture and        continuing mixing; and    -   (5) tabletting the final mixture by compressing it on a suitable        tablet press to produce matrix tablets.

Therefore, the tablets are manufactured via a direct compression processwhich applies to both types of pramipexole extended release matrixtablets. To achieve adequate content uniformity in this low drug loadformulation, the active ingredient is preferably peg-milled. Preferablythe particle size distribution of the peg-milled drug substance, asdetermined by laser diffractometry using a dry dispensing system, ischaracterized by particle fraction of 90% (v/v) being smaller than 100μm, most preferably a particle fraction of 90% (v/v) being smaller than75 μm in diameter.

Also other processes can be applied to the manufacturing of Pramipexoleextended release tablets, like conventional wet granulation and rollercompaction. In case of wet granulation preferably Pramipexole isgranulated with suitable fillers, like, e.g., starches other thanpregelatinized starch, microcrystalline cellulose, lactose monohydrateor anhydrous dibasic calcium phosphate, and wet binding agents, like,e.g., hydroxypropyl methyl cellulose, hydroxypropyl cellulose, povidone,copovidone, and starch paste, leading to a active ingredientconcentrate, which after drying and dry screening is mixed with the mainfraction of gel forming excipients, like all the above describedretarding principles.

In case of roller compaction, or in other words dry granulation, eithera premix of Pramipexole with part of the excipients used in the directcompression process, or the complete mixture containing all excipients,is processed through a conventional roller compactor to form ribbons,which are thereafter screened down to granules which are finally mixedwith other excipients, like glidants, lubricants and antiadherents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram illustrating a preferred embodiment of thedirect compression manufacturing process according to the presentinvention;

FIG. 2 is a graph illustrating the dissolution profiles of a matrixtablet formulation according to the present invention which contains 4%by weight of CARBOPOL® in 3 different pH media; and

FIG. 3 is a graph illustrating the dissolution profiles of 3 matrixtablet formulations according to the present invention which contain 0%,1%, and 4% by weight of CARBOPOL®, respectively.

FIG. 1 illustrates a preferred embodiment of the manufacturing processwith reference to a flow diagram wherein the manufacture of the extendedrelease tablets of Examples 1 and 2 are exemplarily shown. FIG. 1 showsthe detailed process steps and the in process controls performed.

Process step (1) is directed to the active ingredient trituration, i.e.,in the present case a salt of pramipexole, pramipexole dihydrochloridemonohydrate, in peg-milled quality, is preblended with a portion of thepolymer, in this case hydroxypropyl methyl cellulose, in a commonlyknown mixer. In the flow chart, a TURBULA® free-fall mixer or blender isused. The mixing time is several minutes, in the present case preferably10 minutes.

In process step (2) according to the flow chart a premixing isperformed, wherein the active ingredient trituration and the mainportion of the water swelling polymer(s) and excipients are premixed forseveral minutes to obtain a pre-mix. In the present case the mainportion of hydroxypropyl methyl cellulose (hypromellose), corn starch,carbomer 941 and colloidal silicon dioxide are premixed for 5 minutes inthe abovementioned TURBULA® mixer or blender.

According to the following process step (3) a dry screening mayoptionally take place. The pre-mixture may be manually screened througha screen, for example a 0.8 mm mesh size screen, in order to segregatecohesive particles and to improve content uniformity.

In the subsequent process step (4) the main mixing step is performedaccording to which the components are mixed for several minutes,preferably 5 minutes in the TURBULA® mixer after screening. Optionallyfurther excipients may be added at this time, in the flow chart thecomponent magnesium stearate is added to the main mixture, and furthermixing for several minutes, e.g., 3 minutes, in the TURBULA® mixer isperformed (final mixing) to obtain the final mixture.

Process step (5) of the process according to the present invention isthe tabletting. The final mixture is compressed on a suitable tabletpress to produce, for example, oblong shaped matrix tablets (ERtablets=extended release tablets). In order to control and maintain therequired quality the obtained matrix tablets are subjected to thefollowing in-process controls: tablet mass, hardness, tablet height andfriability.

The obtained pramipexole extended release tablets of the presentinvention may then be filled, for example, into high densitypolyethylene (HDPE) bottles. The bottles are closed tightly with screwcaps and appropriately labeled, whereby all packaging and labelingactivities are performed according to cGMP regulations. Alternatively, ablister type packaging can be used, e.g., using aluminum/aluminum foilblisters.

FIG. 2 represents a graph illustrating the dissolution profiles of amatrix tablet formulation according to the present invention. The matrixtablet contains 4% by weight CARBOPOL®, the detailed composition isgiven in Example 2. The release characteristics of the matrix tablet in3 different pH media are shown, i.e., in 0.05 M phosphate buffer,pH=6.8, n=x, in simulated gastric juice, pH=1.2, n=x, and in McIlvainebuffer, pH=4.5, n=x; (x . . . represents the number of units tested).The value percent of released active ingredient is plotted against thetime (hours).

FIG. 3 represents a graph illustrating the dissolution profiles of 3matrix tablet formulations according to the present invention. Thematrix tablets contain no CARBOPOL®, 1% or 4% by weight of CARBOPOL®,respectively, the detailed compositions are given in Examples 1, 2, and4. The medium is a 0.05 M phosphate buffer, pH=6.8. The value percent ofreleased active ingredient is plotted against the time (hours).

FIGS. 2 and 3 show a pH-independent in vitro release characteristic inthe range from pH 1 to 7.5 in case CARBOPOL® is not present and apH-dependent release characteristic wherein the release characteristicin the range of pH <4.5 is faster in case CARBOPOL® is present. Anincrease of the amount of CARBOPOL® leads to a decreased releasing rate.

The advantages of the present invention are manifold. According to thepresent invention, extended release tablets containing pramipexole orits salt are available showing different in vitro release profiles. Itis possible to select a tailor-made release characteristic for patient'sneeds, symptoms, and clinical picture observed.

The primary indication for pramipexole, Parkinson's disease, is anaffliction that becomes more prevalent with advancing age and is oftenaccompanied by decline in memory. Therefore, the matrix tabletsaccording to the present invention providing an extended or slow releaseof pramipexole or a salt thereof allows to simplify the patient'sadministration scheme by reducing the amount of recommended dailyintakes and improves patient's compliance, particularly relevant forelderly patients. The inventive extended release tablet formulationprovides a daily dose preferably administered at one time.

Furthermore, the tablets of the present invention may be manufacturedvia a direct compression, wet or dry granulation process which appliesto both types of extended release matrix tablets.

The invention described will now be illustrated by the Examples whichfollow various other embodiments and will become apparent to the skilledperson from the present specification. However, it is expressly pointedout that the Examples and description are intended solely as anillustration and should not be regarded as restricting the invention.

EXAMPLES

According to the present invention pramipexole extended release tabletshave been manufactured. The tablets of the Examples are white tooff-white, 14×6.8 mm oblong shaped, biconvex tablets. The tablets areintended to be administered orally, and shall not be divided intohalves. The pramipexole tablets in the Examples contain 0.75 mg ofpramipexole dihydrochloride monohydrate, corresponding to 0.524 mg ofpramipexole free, anhydrous base.

Example 1

One embodiment of the qualitative and quantitative composition ofpramipexole extended release tablets according to the present inventionis shown in Table 1.

TABLE 1 Qualitative and Quantitative Composition of Pramipexole ExtendedRelease Tablet mg per 0.75 Reference to Ingredient mg tablet FunctionStandards Pramipexole dihydrochloride 0.750 Active Corporatemonohydrate, peg-milled ingredient standard Hypromellose 2208 157.500Swelling Ph. Eur./USP (Methocel K 15 M) agent Corn starch 183.700 FillerPh. Eur./NF Carbomer 941 3.500 Gelling Ph. Eur./NF (CARBOPOL ® 71 G)agent Colloidal silicon dioxide 2.800 Glidant Ph. Eur./NF Magnesiumstearate 1.750 Lubricant Ph. Eur./NF Total 350.000

Example 2

A further embodiment of the qualitative and quantitative composition ofpramipexole extended release tablets according to the present inventionis shown in Table 2.

TABLE 2 Qualitative and Quantitative Composition of Pramipexole ExtendedRelease Tablet mg per 0.75 Reference to Ingredient mg tablet FunctionStandards Pramipexole dihydrochloride 0.750 Active Corporatemonohydrate, peg-milled ingredient standard Hypromellose 2208 157.500Swelling Ph. Eur./USP (Methocel K 15 M) agent Corn starch 174.600 FillerPh. Eur./USP Carbomer 941 14.000 Gelling Ph. Eur./USP (CARBOPOL ® 71 G)agent Colloidal silicon dioxide 1.400 Glidant Ph. Eur./USP Magnesiumstearate 1.750 Lubricant Ph. Eur./USP Total 350.000

Example 3

The batch formula for the two pramipexole tablet formulations of Example1 and 2 is shown in Table 3. The batch size of the final mixturecorresponds to a batch size of 2000 tablets.

TABLE 3 Composition per Batch of Pramipexole 0.75 mg ER Tablets Gramsper Grams per batch batch Ingredient Example 1 Example 2 Pramipexoledihydrochloride 1.500 1.500 monohydrate, peg-milled Hypromellose 2208315.000 315.000 Corn starch 367.400 349.200 Carbomer 941 7.000 28.000Colloidal silicon dioxide 5.600 2.800 Magnesium stearate 3.500 3.500Total Mass 700.000 700.000

Example 4

The following Example shows a pramipexole tablet formulation whichcorresponds to formulation a) providing a release characteristicindependent in the pH range of 1 to 7.5.

TABLE 4 Constituents mg/tablet Pramipexole-dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2208 (Methocel K 100 M) 157.500 Cornstarch 187.900 Colloidal silicon dioxide 2.100 Magnesium stearate 1.750Total weight matrix tablet 350.000

Example 5

The following Examples 6 to 14 show pramipexole tablet formulationswhich correspond to formulation b) providing a faster releasecharacteristic for pH<4.5.

TABLE 5 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2208 (Methocel K 15 M) 175.000Carboxymethyl cellulose sodium 87.500 Lactose monohydrate (200 mesh)52.500 Microcrystalline cellulose (grade PH 101) 31.100 Colloidalsilicon dioxide 1.400 Magnesium stearate 1.750 Total weight matrixtablet 350.000

Example 6

TABLE 6 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2208 (Methocel K 15 M) 175.000Carboxymethyl cellulose sodium 87.500 Lactose monohydrate (200 mesh)52.500 Microcrystalline cellulose (grade PH 101) 27.600 Carbomer 941(CARBOPOL ® 71 G) 3.500 Colloidal silicon dioxide 1.400 Magnesiumstearate 1.750 Total weight matrix tablet 350.000

Example 7

TABLE 7 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2208 (Methocel K 15 M) 175.000Carboxymethyl cellulose sodium 87.500 Lactose monohydrate (200 mesh)45.500 Microcrystalline cellulose (grade PH 101) 24.100 Carbomer 941(CARBOPOL ® 71 G) 14.000 Colloidal silicon dioxide 1.400 Magnesiumstearate 1.750 Total weight matrix tablet 350.000

Example 8

TABLE 8 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Carbomer 941 (CARBOPOL ® 71 G) 87.500 Lactosemonohydrate (200 mesh) 225.400 Microcrystalline cellulose (grade PH 101)33.200 Colloidal silicon dioxide 1.400 Magnesium stearate 1.750 Totalweight matrix tablet 350.000

Example 9

TABLE 9 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Carbomer 941 (CARBOPOL ® 71 G) 70.000 Lactosemonohydrate (200 mesh) 242.900 Microcrystalline cellulose (grade PH 101)33.200 Colloidal silicon dioxide 1.400 Magnesium stearate 1.750 Totalweight matrix tablet 350.000

Example 10

TABLE 10 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Carbomer 941 (CARBOPOL ® 71 G) 70.000 Lactosemonohydrate (200 mesh) 140.000 Calcium Phosphate, dibasic dihydrate136.100 Colloidal silicon dioxide 1.400 Magnesium stearate 1.750 Totalweight matrix tablet 350.000

Example 11

TABLE 11 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Carbomer 941 (CARBOPOL ® 71 G) 52.500 Lactosemonohydrate (200 mesh) 140.000 Calcium Phosphate, dibasic dihydrate153.600 Colloidal silicon dioxide 1.400 Magnesium stearate 1.750 Totalweight matrix tablet 350.000

Example 12

TABLE 12 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2208 (Methocel K 15 M) 157.500 Corn starch163.400 Carbomer 941 (CARBOPOL ® 71 G) 24.500 Colloidal silicon dioxide2.100 Magnesium stearate 1.750 Total weight matrix tablet 350.000

Example 13

TABLE 13 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2910 (Methocel E 5) 0.788 Corn starch173.812 Hypromellose 2208 (Methocel K 15 M) 157.500 Carbomer 941(CARBOPOL ® 71 G) 14.000 Colloidal silicon dioxide 1.400 Magnesiumstearate 1.750 Total weight matrix tablet 350.000

Example 14

TABLE 14 Constituents mg/tablet Pramipexole dihydrochloride monohydrate,peg-milled 0.750 Hypromellose 2208 (Methocel K 15 M) 148.500 Corn starch160.620 Carbomer 941 (CARBOPOL ® 71 G) 16.500 Colloidal silicon dioxide1.980 Magnesium stearate 1.650 Total weight matrix tablet 330.000

1. An extended release tablet formulation comprising pramipexole or apharmaceutically acceptable salt thereof in a matrix comprising at leastone water swelling polymer other than pregelatinized starch, and whereinthe formulation does not contain pregelatinized starch.
 2. The extendedrelease tablet formulation according to claim 1, wherein the matrixcomprises at least two water swelling polymers other than pregelatinizedstarch, and wherein at least one of the at least two polymers is ananionic polymer.
 3. The extended release tablet formulation according toclaim 1, wherein the at least one water swelling polymer other thanpregelatinized starch is an anionic polymer.
 4. The extended releasetablet formulation according to claim 2 or 3, wherein the anionicpolymer is selected from the group consisting of optionally crosslinkedacrylic acid polymers, methacrylic acid polymers, alginates, andcarboxymethyl cellulose.
 5. The extended release tablet formulationaccording to claim 2 or 3, wherein the anionic polymer is an optionallycrosslinked acrylic acid polymer, and wherein the content of theoptionally crosslinked acrylic acid polymer in the matrix is from about0.25 wt.-% to about 25 wt.-%.
 6. The extended release tablet formulationaccording to claim 5, wherein the anionic polymer is an optionallycrosslinked acrylic acid polymer, and wherein the content of theoptionally crosslinked acrylic acid polymer in the matrix is from about0.5 wt.-% to about 15 wt.-%.
 7. The extended release tablet formulationaccording to claim 6, wherein the anionic polymer is an optionallycrosslinked acrylic acid polymer, and wherein the content of theoptionally crosslinked acrylic acid polymer in the matrix is from about1 wt.-% to about 10 wt.-%.
 8. An extended release tablet formulationcomprising pramipexole or a pharmaceutically acceptable salt thereof ina matrix comprising at least one water swelling polymer other thanpregelatinized starch and optionally excipients, the resulting tabletproviding a pH-independent in vitro release rate in the range from pH 1to 7.5, and wherein the formulation does not contain pregelatinizedstarch.
 9. The extended release formulation of claim 8, whereby the atleast one water swelling polymer is an anionic polymer.
 10. An extendedrelease tablet formulation according to claim 1, 8 or 9, wherein thecontained amount of pramipexole or pharmaceutically acceptable saltthereof is sufficient to provide a daily dose administered at one time.11. A method of manufacturing an extended release tablet formulationcomprising pramipexole or a pharmaceutically acceptable salt thereof ina matrix comprising at least one water swelling polymer other thanpregelatinized starch, and wherein the formulation does not containpregelatinized starch, by a direct compression process comprising thesteps of: (1) producing an active ingredient trituration wherein theactive ingredient is pramipexole or a pharmaceutically acceptable saltthereof by preblending it with a portion of water swelling polymer(s)and/or excipient(s) in a mixer, wherein pramipexole or thepharmaceutically acceptable salt thereof is milled prior to use; (2)premixing the active ingredient trituration of step (1), the mainportion of the water swelling polymer(s) and/or excipients in a mixer toobtain a pre-mixture; (3) optionally dry screening the pre-mixturethrough a screen in order to segregate cohesive particles and to improvecontent uniformity; (4) mixing the pre-mixture of step (2) or (3) in amixer, optionally by adding remaining excipients to the mixture andcontinuing mixing; and (5) tabletting the final mixture by compressingit on a suitable tablet press to produce matrix tablets.
 12. The methodaccording to claim 11, wherein the pramipexole or the pharmaceuticallyacceptable salt thereof is peg-milled prior to use in step (1).
 13. Amethod of manufacturing an extended release tablet formulationcomprising pramipexole or a pharmaceutically acceptable salt thereof ina matrix comprising at least one water swelling polymer other thanpregelatinized starch, and wherein the formulation does not containpregelatinized starch, by a wet granulation process comprising the stepsof: (1) producing an active ingredient trituration wherein the activeingredient is pramipexole or a pharmaceutically acceptable salt thereofby blending it with a portion of the excipients in a mixer, whereinpramipexole or the pharmaceutically acceptable salt thereof is milledprior to use; (2) granulating the active ingredient trituration of step(1) by adding the granulation liquid; (3) drying the granules of step(2) in a fluidized bed dryer or a drying oven; (4) mixing the driedgranules of step (3) with the water swelling polymer(s) and/orexcipients in a mixer to obtain the final mixture; and (5) tablettingthe final mixture of step (4) by compressing it on a suitable tabletpress to produce matrix tablets.
 14. The method according to claim 13,wherein the pramipexole or the pharmaceutically acceptable salt thereofis peg-milled prior to use in step (1).
 15. The method according toclaim 13, wherein the granulation liquid of step (2) is water.
 16. Amethod of manufacturing an extended release tablet formulationcomprising pramipexole or a pharmaceutically acceptable salt thereof ina matrix comprising at least one water swelling polymer other thanpregelatinized starch, and wherein the formulation does not containpregelatinized starch, by a dry granulation process comprising the stepsof: (1) mixing the active ingredient pramipexole or a pharmaceuticallyacceptable salt thereof with either a portion of the fillers or all theexcipients in a mixer, wherein pramipexole or the pharmaceuticallyacceptable salt thereof is milled prior to use; (2) compaction of themixture of step (1) on a suitable roller compactor; (3) reducing theribbons obtained during step (1) to small granules by suitable millingor sieving steps; (4) optionally mixing the granules of step (3) withthe remaining excipients in a mixer to obtain the final mixture; and (5)tabletting the granules of step (3) or the final mixture of step (4) bycompressing it on a suitable tablet press to produce matrix tablets. 17.The method according to claim 16, wherein the pramipexole or thepharmaceutically acceptable salt thereof is peg-milled prior to use instep (1).